PT2670751E - Methods of making hiv attachment inhibitor prodrug compound and intermediates - Google Patents

Description

DESCRIPTION

METHODS OF MANUFACTURE OF A PROFARMACO COMPOUND INHIBITOR OF HIV FIXATION AND INTERMEDIARIES

FIELD OF THE INVENTION

The invention relates to methods of manufacture of prodrugs useful against HIV and in particular to methods of manufacture of the prodrug 1-benzoyl-4- [2- [4-methoxy-7- (3-methyl-1H- 1,2-triazol-1-yl) -1 - [(phosphonooxy) methyl] -1H-pyrrolo [2,3-c] pyridin-3-yl] -1,2-dioxoethyl] piperazine, as well as certain intermediates thereof, using novel alkylation, amidation, chlorination and phosphate installation strategies. The invention also relates to the compounds obtained by the processes set forth herein. The prodrug compound inhibitory of HIV binding identified as 1-benzoyl-4- [2- [4-methoxy-7- (3-methyl-1H-1,2,4-triazol-1-yl) -1- - [(phosphonooxy) methyl] -1A-pyrrolo [2,3-c] pyridin-3-yl] -1,2-dioxoethyl] -piperazine, and having the structural formula:

has been disclosed and described in U.S. Patent No. 7,745,625, which is incorporated herein in its entirety. This compound is the phosphate drug of the basic compound having the structural formula:

which is disclosed and described in U.S. Patent No. 7,354,924, also incorporated herein in its entirety. Both this compound and the prodrug identified above have so far demonstrated excellent ability against HIV.

During the step procedures for the production of the prodrug compound phosphate, two compounds were used in the alkylation process between phosphonic acid, P- (chloromethyl) -, bis (1,1-dimethylethyl) ester and 1- ( 4-methoxy-7- (3-methyl-1H-1,2,4-triazol-1-yl) -1H-pyrrolo [2,3-c] pyridin- 3-yl] ethan-1,2-dione. However, these compounds have been shown to be difficult to process, or unstable and difficult to obtain at scale. has been changed in scale.What is now required in the art are novel processes for making the prodrug compound of HIV 1-benzoyl-4- [2- [4-methoxy-7- (3-methyl-1H-1,2,4 1-yl) -1 - [(phosphonooxy) methyl] -1H-pyrrolo [2,3-c] pyridin-3-yl] -1,2-dioxoethyl] piperazine, as well as intermediate compounds. different alkylation, amidation, chlorination and It also requires new compounds and intermediates that are generated as a result of the new processes.

SUMMARY OF THE INVENTION

In a first embodiment, the invention provides a method for making the compound of Formula I:

with the chemical name 2-amino-2- (hydroxymethyl) propan-1,3-diol- (3- (2- (4-benzoylpiperazin-1-yl) -2-oxoacetyl) -4-methoxy-7- (3-methyl-1H-1,2,4-triazol-1-yl) -1H-pyrrolo [2,3-c] pyridin-1-yl) methyl which comprises: (a) brominating the compound

to produce the compound and

(b) nitrating compound 2 to produce the compound and

(c) converting the amine group of compound 3 to a methoxy group to produce the compound and

(d) then converting compound 4 to compound e

(e) converting compound 5 into the compound

and

(f) forming a bicyclic structure from compound 6 to afford and (g) then chlorinating compound 7 to afford

and

(h) thereafter adding a triazolyl residue to compound 8 to produce and (i) converting compound 9 into the structure and

(j) modifying compound 10 to produce the compound and

(k) reacting compound 11 to produce the compound and

(1) then converting compound 12 to compound e

(m) then reacting compound 13 to give

compound and (n) then reacting compound 14 to give

compound and (or) then converting compound 15 to the compound of Formula I.

In a further embodiment of the invention, there is provided a method of making the compound of Formula I:

which comprises: (i) reacting the compound with

in the presence of TMG, NMP and Nal or K2CO3, MeCN and TBA1 to produce the compound

and (ii) reacting compound 11 with

to produce the compound and

(iii) then convert the

compound 12 to compound (iv) and then reacting compound 13 to produce

and (v) then reacting compound 14 to produce the compound and

then converting compound 15 to the compound of Formula I.

Also provided herein is a method of making the compound of formula (14):

which comprises: (i) reacting the compound with

to produce the compound and

(ii) reacting compound 11 to produce the compound and (iii) then converting compound 12 to compound

(iv) and then converting the compound (13) into the compound

The invention is also directed to the more general chemical transformation of converting a thioether to the corresponding chloride using a chlorinating agent.

wherein R may be, but is not limited to alkyl, cycloalkyl, phenyl, substituted and polysubstituted phenyl rings, heteroaromatic rings, substituted and polysubstituted heteroaromatic rings. The chlorinating agent used in this transformation may be, but is not limited to, chlorine gas, sulfuryl chloride, hexachloroethane, dichlorotriphenylphosphorane, N, N-dichloro-4-methylbenzenesulfonamide, trichloroisocyanuric acid, N-chlorosuccinimide, 2-chloroisoindolin-1,3 -dione or N-chlorosaccharin. The invention is also directed to novel compounds

The invention is directed to these and other important purposes, described hereinafter. DETAILED DESCRIPTION OF THE EMBODIMENTS The invention provides methods for the production of the compound of Formula I:

as well as certain intermediates. The overall reaction scheme can be summarized and explained as follows:

Therefore, in a first embodiment the compound

is used as the starting material. This compound is reacted with acetic anhydride (Ac 2 O) and then brominated to yield

This compound is then reacted with nitric acid and with sulfuric acid to afford

Subsequently, this compound is then reacted with sodium nitrate (NaNO 2) and trimethylsilyl chloride (TMS-Cl 2) in methanol (MeOH) to afford

This compound is then reacted with to produce

which is then reacted with a mixture of NaOMe / MeOH, Cul and NH4 Cl in tetrahydrofuran (THF) and methyl propionate to afford

This compound is then reacted with 1% Pd / C in an atmosphere of hydrogen gas (H2) in ethyl acetate (EtOAc) to afford

which is further reacted with POCl 13 to produce

This resulting compound is reacted with three (3) equivalents of

in 4-Me-2-pentanol to afford

This compound is then reacted with

in iPrMgCl and THF to obtain

This compound is then reacted with

and tetrametylguanidine (TMG) in N-methylpyrrolidone (NMP) or K 2 CO 3 in MeCN to obtain

This compound is then reacted with

in Ti (0nBu) 4 and MeTHF to produce

This compound is then chlorinated using chlorine gas (Cl 2) to afford

This compound is then reacted with dichloromethane (DCM) in water to afford

This compound is further reacted with to obtain

Finally, there is an additional reaction with acetone in water, then in tromethamine to produce the prodrug

In a further embodiment of the invention, the compound of Formula I above is produced using

as the starting material. This compound may be synthesized according to the procedures detailed above, or may be obtained according to the procedures explained and described in U.S. 20060293304, December 28, 2006, which is hereby incorporated by reference in its entirety.

In this embodiment,

is reacted first with

in the presence of TMG, NMP and Nal or K2CO3, MeCN and TBA1 to produce the compound

This compound is then reacted with

to afford the title compound

This compound is then converted to the compound

using chlorine gas (Cl2). Subsequently, this compound is converted into

using dichloromethane in water. This compound is then reacted to produce the compound using

and finally, this compound is then converted to the compound of Formula I with acetone in water, and then with tromethamine.

In a further embodiment of the invention, the compound of formula (14) is manufactured using the compound of formula (10) as the starting material. This process involves reacting the compound with

to afford the title compound

and then reacting compound 11 to give compound

Then, compound 12 is converted to compound

Subsequently, compound 13 is converted to compound

Compounds 11, 12, 13 and 14 are further embodiments of the invention. The following Example explains a preferred method of the invention, but should not be construed as limiting the scope thereof:

EXAMPLE

In this Example, the compound

was used as the starting material (see U.S. 20060293304, December 28, 2006 to produce compound 10). the following is the summary of the procedure for converting compound 10 into compound 11:

• A reaction vessel of 20 l and 10 l was purged with inert gas. All steps were performed with inert gas protection. The 20 L reactor was charged with 1.80 L of ethyl acetate at room temperature. To this was added 0.48 ka of the compound

To this solution was added 0.34 kg of sodium iodide. All the glass material used in the additions was then washed with 0.45 l of ethyl acetate which was also charged into the 20 l reactor. The reaction mixture was heated to an internal temperature of 65 ° C and stirred there temperature for 3 hours. • A sample of the reaction mixture was analyzed by NMR ΤΗ to determine the conversion of in

If the conversion is not greater than 90%, the heating is continued. • After completion, the solution of

allowed to cool to room temperature. To a 10 L vessel was added 1.58 L of N-

Methylpyrrolidone (NMP) followed by 0.18 kg of N, N, N ', N'-tetramethylguanidine (TMG). To this solution was charged 0.45 kg of compound 10. Finally all of the glass material used for the additions was rinsed with 0.50 1 of NMP. The mixture was stirred at room temperature for 2 hours. • The NMP solution in the 10 1 reactor was then transferred to the EtOAc solution of

for 1 hour. The flask was rinsed with 0.18 ml of NMP which were also added to the solution for 2 minutes.

The resulting mixture was stirred at room temperature for 1 hour. • A sample of the reaction mixture was collected for monitoring by high pressure liquid chromatography (HPLC). To the reaction was added a total of 0.099 kg of TMG in 10 equal portions for 2 hours and the resulting mixture was stirred at room temperature for 14 hours. • A sample of the reaction mixture was collected for HPLC monitoring. To the reaction was charged 6.75 1 EtOAc followed by 4.51 L of 0.5 N aqueous hydrochloric acid solution (HCl). The mixture was stirred vigorously for 30 minutes and then allowed to settle and phase of the fund was discarded. To the remaining top phase 2.50 L of EtOAc was added, followed by the slow addition of 4.50 L of 0.5 N HCl. The biphasic mixture was stirred vigorously for 15 minutes and then allowed to settle and background phase was discarded. The remaining top phase was added 0.50 L of EtOAc followed by the slow addition of 4.50 L of 0.5 N HCl. The biphasic mixture was stirred vigorously for 15 minutes and then allowed to settle and background phase was discarded. To the remaining upper layer were added 1.10 L of EtOAc followed by the addition of 4.50 L of distilled water. The biphasic mixture was stirred vigorously for 15 minutes and then the phases were allowed to settle and the bottom phase was discarded. To the remaining upper layer 0.51 EtOAc was added followed by the addition of 4.50 L of distilled water. The biphasic mixture was stirred vigorously for 15 minutes and then the phases were allowed to settle and the bottom phase was discarded. The final organic stream was transferred gradually to a reactor of 10 1 in increases of 4.00 1 with a wash of 1.01 of EtOAc of the reactor of 20 1 and between each charge the volume of the stream was reduced to 3, 60 1 by solvent distillation. The composition of the solvent was changed after essentially EtOAc to essentially isopropyl alcohol (IPA) using a stripping distillation and for a total of 9.00 l of IPA and never allowing the total reaction volume to drop below 3.60 1. The final solution was allowed to age for 8 hours. The resulting suspension was filtered to isolate the product. The product was then washed twice with 1.12 L of IPA. The isolated product was dried at a maximum temperature of 50 ° C until reaching a constant weight. The yield was 0.43 kg (63.23%) of compound 11 as beige crystals. • Analytical data: mp 127.0 - 128.8 ° C. 1 H-NMR (

(S, 1H), 7.93 (s, 1H), 7.25 (d, J = 8.5 Hz, 2H), 5.60 (s, 2H), 4.10 (s, 3H), 3.95 (s, 3H), 2.58 (d, J = (s, 3H). (Δ, ppm): 181.4, 165.1, 162.0, 152.1, 147.4, 142.7, 136.3 (3C), 130.6, 130.4 (2C), 129.9, 127.9, 126.8, 122.8, 114.3, 57.3, 56.7, 53.3, 13.3. HRMS: Calculated for C 21 H 194 N 5 CIS [M + 1] + 472.0841 found 472.0841.

Analysis of elements: C: 53.44, H: 3.84, N: 14.84, S: 6.79, Cl: 7.51; Found: C: 53.53, H: 3.55, N: 14.63, S: 6.98, Cl: 7.73. The procedure was then continued as follows with a summary of the conversion of compound 11 into compound 12 as explained below:

• A reaction vessel was purged with inert gas.

All steps were performed with inert gas protection. The vessel was then charged with 8.0 l of MeTHF at 20-25 ° C. Then, 800 g of compound

A white suspension is formed. To the suspension was charged 488 ml of water and 388 ml of 1N NaOH. No exotherm was observed. The stirring was removed after 1 hour and the layers were allowed to settle. The aqueous layer was removed from the bottom. The remaining organic layer was heated to reflux and approximately 31 L of MeTHF was distilled. At this point the distillation was carried out under constant volume conditions. • When a KF < 500 ppm the mixture was allowed to cool to room temperature. The organic layer was filtered and the benzoyl piperazine concentration was measured. • A separate vessel was purged with inert gas. • In the vessel 5.2 1 of the previous solution of compound

(1.3 eq.). To this followed the addition of 1 kg of compound 11 which was charged resulting in a white suspension. Finally, 260 ml of Ti (OnBu) 4 and 800 ml of MeTHF were charged. The mixture was heated to reflux. After 3 hours the mixture was seeded with 2 g of the compound of formula 11. The reaction was allowed to proceed to reflux. After completion, the suspension was cooled to 10 ° C and allowed to stir for 2 hours. The product was filtered, washed with 2 ml of MeTHF and then 3.15 L of EtOH. The product was dried at 50 ° C in a vacuum oven until a constant weight was reached. The yield was 1.07 kg (80.4%) of pearl white crystals of compound of formula 12. • Analytical data: mp 162 ° C. NMR (CDCl 3) δ, ppm): 2.54 (s, 3H), 3.52 (bs, 4H), 3.74 (bs, 4H), 4.08 (s, 3H) (D, J = 8.2 Hz, 2H), 7.2 (d, J = 8.8 Hz, 2H), 7.44 (bs, 5H) (S, 1H), 7.91 (s, 1H), 8.62 (s, 1H): 13 C NMR (CDCl3) (δ, ppm): 13.91, 41.6, , 5. 56.8, 114.3, 122.3, 125.1, 126.7, 127.0, 128.64, 129.5, 129.6, 129.8, 130.2, 134.9 , 135.2, 135.7, 140.8, 145.5, 150.6, 161.9, 165.9, 170.6, 184.4; HRMS; Calc'd for C 31 H 29 ClN 7 O 4 S [M + 1] +: 630.1685; found: 630.1688. Analysis of elements: C: 59.99, H: 4.47, N: 15.56, S: 5.08, Cl: 5.62; Found: C: 59.05, H: 4.28, N: 15.57, S: 5.07, Cl: 5.66. The procedure was then continued as follows, with a summary of the process for the conversion of compound 12 to compound 14 as explained below:

• A reaction vessel was purged with inert gas. All steps were performed with inert gas protection. The vessel was then charged with 5 l of dichloromethane at 20-25 ° C. Then, 1.00 kg of the compound of formula 12 was added to the vessel to give a colorless reaction. The solution was then cooled to 0 ° C (-3 to 3 ° C), followed by the subsurface addition of 113 g of chlorine. An orange solution formed and the reaction was observed to be exothermic. The temperature was maintained at about 0 ° C (-3 to 3 ° C). • A sample was collected for monitoring by high pressure liquid chromatography (HPLC) and additional chlorine loads were added as needed. • After the completion of the reaction, the solution was heated to 15 ° C. • A solution of isopropanol (1.0 eq.) And 10 l of acetone was prepared. The 5% by volume of this solution was added to the vessel for approximately 30 minutes to give a pale yellow suspension.

After a time of 30 minutes, 95% by volume

of the isopropanol / acetone solution was added over 2 hours to give a white suspension. This addition was slightly exothermic and some cooling was required (Tmax = 25 ° C). The suspension was aged at 20øC and HPLC was used to monitor the progress of crystallization. The product 13 was then filtered, and washed with 5 L of acetone: dichloromethane 2: 1 (v: v), followed by 2.5 L of acetone. The product 13 could then be dried at a maximum temperature of 50 ° C until reaching a constant weight or bringing the wet cake back to product 3. For the insulation 13 the yield was 0.78 kg (88% ) as white crystals. • For the isolation of 14, a second reaction vessel was purged with inert gas. The vessel was then charged with 5 l of dichloromethane at 20-25 ° C. Then approximately 1.10 kg of the wet cake compound of formula 13a was added to the vessel to give a white suspension, followed by the addition of 5 L of water. A biphasic solution formed and the temperature was maintained at about 22øC (20 to 25øC). • A phase breakdown was performed, and the product-rich lower organic layer was then charged with 1.5 L of ethyl acetate under constant volume distillation conditions (pressure = 40 kPa). The resulting solution was then seeded with 13b and aged for 30 minutes. Further 9-12 L of additional ethyl acetate was added under constant volume distillation conditions (pressure drop to <10 kPa.) The suspension was aged at 20 ° C and HPLC was used to monitor the progress of the crystallization. The product 14 was then filtered and washed with 4 L of ethyl acetate • Product 14 was then filtered at a maximum temperature of 50 ° C until reaching a constant weight • For the isolation of 14 the yield was 0, 70 kg (85%) as white crystals Analytical data for 13: mp 121 DEG C. RMIST-1 (d7-DMF)

(δ, ppm): 11.17 (br s, 1H), 9.18 (s, 1H), 8.88 (s, 1H), 8.19 (s, 1H), 7.52-7.54 (m, 5H), 6.44 (s, 2H), 4.19 (s, 3H), 3.67-3.84 (m, 8H), 2.55 (s, 3H); 13 C NMR (d 7 -DMF) (δ, ppm): 185.4, 169.9, 166.2, 161.3, 151.1, 146.6, 142.3, 136.1, 129.9, 129.5, 128.6, 127.3, 127.2, 124.7, 123.4, 116.1, 57.7, 56.9, 45.9, 41.7, 13.1; HRMS calc for C 25 H 25 ClH 7 O 4 [M-Cl] +: 522.1578 found 522.1648. Analysis of elements: C: 53.77, δ: 4.51, δ: 17.55, Cl: 12.69, found: C: 53.05, δ: 4.68, δ: 17.20, Cl: 12.56. • Analytical data for 14: mp 211 ° C. 1 H NMR (CDCl 3) (δ, ppm): 8.59 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.41 (s, 09 (s, 2H), 4.04 (s, 3H), 3.40-4.00 (m, 8H), 2.51 (s, 3H); NMR (CDCl 3) (δ, ppm): 184.4, 170.6, 165.7, 162.1, 150.6, 145.6, 140.8, 134.8, 130.1, 129.6, 128.6, 127.0, 126.7, 125.1, 122.9, 116.1, 57.1, 56.8, 45.9, 41.7, 13.9; HRMS calc for C 25 H 25 ClH 7 O 4 [M + H] +: 522.1578 found 522, 1653. Analysis of elements: C: 57.52, H: 4.64, N: 18.78, Cl: 6.79, found: C : 57.26, H: 4.60, N: 18.44, Cl: 7.14. The process was then continued as follows, with a summary of the process for the conversion of compound 14 into compound 15 as explained below.

• A reaction vessel was purged with inert gas. All steps were performed with inert gas protection. The vessel was then charged with 3 L of dichloromethane at 20-25 ° C. 1.00 kg of compound of formula 14, 0.20 kg of tetramethylammonium bromide (0.50 eq.) And 0.5 l of dichloromethane were added to the vessel to give a colorless solution. The solution was then heated to 35øC (33 to 37øC) and charged with 0.57 kg of di-tert-butyl potassium phosphate (1.2 eq) in 4 x 0.3 eq. portions for 1 h, followed by 0.5 l of dichloromethane. A yellow suspension formed and the reaction was heated at 40 ° C (38 to 42 ° C). • A sample was collected for monitoring by high pressure liquid chromatography (HPLC) and was added if di-tert-butyl potassium phosphate was required. After the completion of the reaction, the slurry was cooled to 20 ° C. The vessel was then charged with 5 l of water and the resulting biphasic solution was maintained at about 20 ° C (18 to 22 ° C). • A phase breakdown was performed, and the product-rich lower organic layer was then charged with 51 l of tert-butyl methyl ether: isopropanol 20: 1 (v: v). The solution was then seeded with compound 15 and aged for 30 min. Additional 11 1 tert -butylmethyl ether: isopropanol 20: 1 (v: v) was then added over 3 hours. The suspension was aged at 20 ° C and HPLC was used to monitor the progress of crystallization. • Compound 15 was then filtered and washed with 51 l of tert-butyl methyl ether: isopropanol 20: 1 (v: v)]: dichloromethane 4: 1 (v: v), followed by 51 l of tert.- butylmethyl. Compound 15 was then dried at a maximum temperature of 50 ° C until reaching a constant weight. • For the isolation of compound 15, the yield was 1.13 kg (85%) as white crystals. • Analytical data for 2: mp 198 ° C. NMR (CDCl 3) δ, ppm): 8.51 (s, 3H), 8.17 (s, 3H), 7.88 (s, 3H), 7.39 (m, 5H) 2H), 4.03 (s, 3H), 3.30-3.80 (m, 8H), 2.47 (s, 3H), 1.25 (s, 18H) ); 13 C NMR (CDCl 3) (δ, ppm): 184.6, 170.5, 166.8, 161.4, 150.7, 145.3, 141.8, 134.9, 130.1, 5, 128.5, 127.5, 127.0, 124.6, 122.6, 115.1, 83.7 (d, J = 7.4

(D, J = 6.6 Hz), 56.8, 45.9, 41.6, 29.5, (d, J = 4.4 Hz), 13.8, 31P (CDCl3) (δ, ppm): -10.0; HRMS: calculated for C33 H43 N7 O8 P [M + H] +: 696.2832 found 696.2885. Analysis of elements: C: 56.97, H: 6.08, N: 14.09, found C: 57.00, H: 6.04, N: 14.13. The above process may be continued as explained herein in the description to produce the compound of Formula I. The compound of Formula I, once synthesized, may be used in compositions for treating HIV infection as is explained and described in Patents Nos. 7,745,625, 7,354,924 and 7,776,863, by way of non-limiting examples.

DOCUMENTS REFERRED TO IN THE DESCRIPTION

This list of documents referred to by the author of the present patent application has been prepared solely for the reader's information. It is not an integral part of the European patent document. Notwithstanding careful preparation, the IEP assumes no responsibility for any errors or omissions.

Patent References Referred to in the Description • US 7745625 B • U.S. Pat. No. 4,745,625 B • U.S. Pat.

Lisbon, June 18, 2015

Claims (18)

A method for making the compound of Formula I: comprising: (a) brominating the compound to afford the title compound and (b) nitrating compound 2 to produce the compound and (c) converting the amine group of compound 3 to a methoxy group to produce the compound (d) then converting compound 4 to compound e (e) converting compound 5 into the compound and (f) forming a bicyclic structure from compound 6 to afford and (g) then chlorinating compound 7 to afford and (h) thereafter adding a triazolyl residue to compound 8 to afford and (i) converting compound 9 into the structure and (j) modifying compound 10 to produce compound and (k) reacting compound 11 to produce compound and (l) converting compound 12 to compound (m) then converting compound 13 to compound and (n) then reacting compound 14 to produce the compound and (or) then converting compound 15 to the compound of Formula 1. A method of making the compound of Formula I: (i) reacting the compound with in the presence of TMG, NMP and Nal or K2CO3 and MeCN to afford compound and (ii) reacting compound 11 with to afford the title compound and (iii) converting compound 12 to compound (iv) then converting compound 13 to compound and (v) then reacting compound 14 to produce the compound and (vi) then converting compound 15 to the compound of Formula I. The method of claim 1, wherein step (a) is performed using AC2O. The method of claim 1, wherein step (b) is performed under acidic conditions. The method of claim 4, wherein step (b) is performed using nitric acid. The method of claim 5, wherein step (b) is performed using nitric acid and sulfuric acid. The method of claim 1, wherein step (c) is performed using NaNO 2 and TSM-Cl in alcohol. The method of claim 7, wherein said alcohol is methanol. The method of claim 1, wherein step (d) is performed using The method of claim 1, wherein step (h) is performed using The method of claim 1, wherein step (i) is performed using The method of claim 1, wherein step (j) is performed using The method of claim 2, wherein step (ii) is performed using The method of claim 2, wherein step (iv) is performed using dichloromethane. The method of claim 2, wherein step (v) is performed using The method of claim 2, wherein step (vi) is performed using acetone in water and tromethamine. A method of making the compound of formula (14): which comprises: (i) reacting the compound with to afford the title compound and (ii) reacting compound 11 with to afford the title compound and (iii) then converting compound 12 to compound using chlorine gas; (iv) then produce compound 14 using dichloromethane. 18. The compound having the following formula: Lisbon, June 18, 2015